Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors
Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors
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DOI：
10.1073/pnas.2002082117
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发表时间：
2020-06-02
影响因子：
11.1
通讯作者：
Chen, Jichao
中科院分区：
文献类型：
--
作者：
Gerner-Mauro, Kamryn N.;Akiyama, Haruhiko;Chen, Jichao
在多细胞生物中，来自基因复制的旁系同源物通过进化组织特异性表达和功能而在净化选择中存活。对于多成员旁系同源物，这种遗传冗余是否也在单细胞类型内被选择尚不清楚，如典型Wnt信号传导的四个强制性Lef/Tcf转录因子所例示的，这主要是由于所涉及的复杂遗传学。使用发育中的小鼠肺作为模型系统，我们产生了两个四重条件敲除，四个三重突变体，和各种组合的双突变体，显示四个Lef/Tcf基因功能冗余的存在下，至少有两个Lef/Tcf旁系同源物，但添加后失去额外的旁系同源物，以指定和维持肺上皮祖细胞。prelung规范，泛上皮双敲除没有肺表型;三重敲除有不同的表型，包括有缺陷的分支和气管食管瘘;和四重敲除几乎没有形成一个肺，类似于Ctnnb 1突变。所有四个Lef/Tcf基因的肺后特异性缺失导致分支缺陷、祖细胞基因下调、过早肺泡分化和胃肠基因去阻遏，再次表型模仿相应的Ctnnb 1突变体。我们的研究支持CTNNB 1和Lef/Tcf在肺上皮祖细胞中的单调，正信号关系，而不是报道的Lef/Tcf的阻遏功能，并代表了四个Lef/Tcf旁系同源物之间细胞类型特异性遗传冗余的彻底体内分析。
In multicellular organisms, paralogs from gene duplication survive purifying selection by evolving tissue-specific expression and function. Whether this genetic redundancy is also selected for within a single cell type is unclear for multimember paralogs, as exemplified by the four obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the complex genetics involved. Using the developing mouse lung as a model system, we generate two quadruple conditional knockouts, four triple mutants, and various combinations of double mutants, showing that the four Lef/Tcf genes function redundantly in the presence of at least two Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Prelung-specification, pan-epithelial double knockouts have no lung phenotype; triple knockouts have varying phenotypes, including defective branching and tracheoesophageal fistulas; and the quadruple knockout barely forms a lung, resembling the Ctnnb1 mutant. Postlung-specification deletion of all four Lef/Tcf genes leads to branching defects, down-regulation of progenitor genes, premature alveolar differentiation, and derepression of gastrointestinal genes, again phenocopying the corresponding Ctnnb1 mutant. Our study supports a monotonic, positive signaling relationship between CTNNB1 and Lef/Tcf in lung epithelial progenitors as opposed to reported repressor functions of Lef/Tcf, and represents a thorough in vivo analysis of cell-type-specific genetic redundancy among the four Lef/Tcf paralogs.